The Mad Cow Virus?

Viruses Are Cool #9
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One of the peculiarities of infectious disease news reporting is the rotation of various pathogens through the media spotlight as they come into, and fall out of, fashion. It is thus that mad-cow disease, which once enjoyed front-page status, now finds itself relegated to a brief note despite having caused two recent deaths in Spain. But although mad-cow disease has been largely overshadowed by newer pathogens du jour, the debate over how exactly it is caused appears to be alive and well.

Mad-cow disease, or bovine spongiform encephalopathy (BSE), is one of several prion diseases collectively known as transmissible spongiform encephalopathies (TSEs), which often present with neurological symptoms including dementia, ataxia, and behavioral changes. Animal TSEs include BSE, which afflicts cattle, and scrapie in sheep. Human TSEs exist in several varieties including (1) Creutzfeldt-Jakob disease (CJD), which can be iatrogenic, familial, sporadic or new variant (acquired from consumption of meat from animals with BSE), (2) fatal familial insomnia, which is hereditary, and (3) kuru, which is believed to have spread amongst tribal people of Papua New Guinea through cannibalistic rituals.

What is remarkable about prion disease is that the "infectious particle" is believed to be protein with no accompanying nucleic acid, in contrast to viruses which carry their genetic material in DNA or RNA form. The pathology of prion disease is thought to be caused by misfolding of the cellular protein, PrP^c, into a pathogenic form called PrP^sc. The "infection" then spreads as PrP^sc molecules interact with PrP^c molecules and promote their conversion to the pathogenic form¹. This "protein-only" model for prion pathogenesis was both novel and highly controversial when first proposed, and even suggested a pseudo-Lamarckian form of inheritance in the non-genetic replication of an acquired characteristic, namely the PrP^sc conformation. The development of this model of prion pathogenesis earned Stanley Prusiner the 1997 Nobel Prize in Physiology & Medicine.

In spite of this, and even though the protein-only model is now generally accepted, some scientists still contend that a virus might be the transmissible agent of TSEs. Some theories that have been put forth, which are not necessarily mutually exclusive, are: (1) PrP is a susceptibility gene for infection with the TSE agent, (2) PrP is bound to nucleic acid which encodes the genetic material of the TSE agent, and (3) infection with the TSE agent promotes misfolding and/or aggregation of PrP. But over a decade of searching has yet to identify a virus which can be conclusively demonstrated to cause TSE.

However, proponents of the viral etiology model of prion pathogenesis received a boost from a PNAS paper last year in which the authors describe the production of 25nm virus-like particles in cells infected with scrapie or CJD samples. These particles have also previously been observed in brain tissue from diseased animals. The particles do not co-localize with PrP aggregates in the cells and are not labeled by anti-PrP antibodies, suggesting that they are not prions. Moreover, phorbol ester stimulation, which increases production of abnormal PrP aggregates, does not alter either the production of these virus-like particles or the infectious titer of the cells. These data, combined with the previous demonstration that prion infectivity is abrogated by disruption of nucleic acid-protein interactions, suggest the possibility that these virus-like particles are the etiologic agent of prion disease.

Whether this idea will gain more widespread acceptance remains to be seen. At the very least, these virus-like particles will have to be purified and shown to cause prion disease upon experimental infection of animals. But from a virologist's standpoint, this an exciting possibility. After all, viruses are thought to be involved in all kinds of diseases including cancer, autoimmunity, allergy, and even obesity. Why not prion diseases?

¹Figure from "Prion", Wikipedia.

Tangled Bank 103